The present invention relates to therapeutic pharmaceutical agents which are activated intracellularly by reaction with cellular electron carriers or free radicals to cause release of a free and active drug molecule.
The effects of the preponderance of drugs result from their interaction with functional macromolecular components of the organism. Such interaction alters the function of the pertinent cellular component and thereby initiates the series of biochemical and physiological changes that are characteristic of the response to the drug. The term receptor denotes the component of the organism with which the chemical agent interacts. There are fundamental corollaries to the statement that the receptor for a drug can be any functional macromolecular component of the organism. One is that a drug is potentially capable of altering the rate at which any bodily function proceeds; a second is that, by virtue of interactions with specific receptors, drugs do not create effects but merely modulate the rates of ongoing functions. A simple pharmacological dictum thus states that a drug cannot impart a new function to a cell. Functional changes due to a drug result from either enhancement or inhibition of the unperturbed rate. Furthermore, a drug that has no direct action can cause a functional change by competition for a binding site with another, active regulatory ligand of the receptor. Drugs are termed agonists when they cause effects as a result of direct alteration of the fundamental properties of the receptor with which they interact. Compounds that are themselves devoid of intrinsic pharmacological activity but cause effects by inhibition of the action of a specific agonist (eg. by competition for agonist binding sites) are designated as antagonists.
At least from a numerical standpoint, the proteins of the cell form the most important class of drug receptors. Obvious examples are the enzymes of crucial metabolic or regulatory pathways (eg., tyrosine hydroxylase; 3-hydroxy-3-methylglutaryl-CoA reductase), but of equal interest are proteins involved in transport processes (eg. Ca2+- ATPase; Na+- K+- ATPase) or those that are protein kinases which activate other proteins as a consequence of their binding a secondary messenger such as cAMP. Specific binding properties of other cellular constituents can be exploited. Thus, nucleic acids are important drug receptors, particularly for chemotherapeutic approaches to the control of malignancy, and plant lectins shown remarkable specificity for recognition of specific carbohydrate residues in polysaccharides and glycoproteins: Small ions such as Ca2+which can function as a regulatory ion or Fe2+which can serve as an essential enazmatic cofactor can be exploited as drug receptors. And, drugs can also produce a functional change by a nonreceptor-mediated action. Certain drugs that are structural analogues of normal biological constituents may be incorporated into cellular components and thereby alter their function. This has been termed a xe2x80x9ccounterfeit incorporation mechanismxe2x80x9d and has been implemented with analogues of purines and pyrimidines that can be incorporated into nucleir acids and that have utility in cancer chemotherapy and that have antiviral activity. Also, specific constituents of pathogens can be exploited as receptors. For example, the electron carriers of bacterial can serve as receptors as described in my previous U.S. Patent Application Ser. No. 948,326, and the replicative enzymes of viruses can be serve as receptors as described below for the virus HIV. Many compounds are known which have receptor or nonreceptor mediated in vitro activity as appears in Handbook of Enzyme Inhibitors, Mahendra Kumor Jain, 1982, Wiley Interscience, New York, hereby incorporated by reference. However, only a small percentage produce the desired functional change in vivo or have a high therapeutic ratio because they are toxic in their free form; they are rapidly inactivated or excreted; or, they cannot obtain access to their target receptor or site of action because they are impermeant to cells or biological barriers such as the blood brain barrier due to unfavorable energetics due, for example, to the possession of polar or charge groups; or, they are toxic as a consequence of being nonselective with regards to their access to and action with receptors in one biological environment or compartment relative to another. In these cases, compounds which demonstrate in vitro efficacy are ineffective therapeutics.
A broad class of pharmaceutical agents is disclosed herein as the Luminide class of pharmaceuicals. Luminide agents are three part or four part molecules where each part is a functionality with a defined purpose. Exemplary Luminides are 
where A represents a functionality which is activatable by the environment and capable of transferring energy from its own excited state to the B functionality which is an energy acceptor. Upon receiving energy from A, B achieves an excited state which relaxes through the heterolytic cleavage of the covalent bond of B with C where C is a drug moiety which is released into the intracellular compartment where activation of A occured. Released C can act locally or at a distant site. D serves as an electron transfer functionality which gains (loses) electrons from (to) the environment and donates (accepts) electrons to (from) A to activate it so that the energy of excited A is transferred to B with release of C as occurs for the three functionality case.
In both cases, free C is a drug molecule. The released drug molecule effects a therapeutic functional change by a mechanism which comprises receptor mediated mechanisms including reversible or irreversible competitve agonism or antagonism including a suicide substrate or transition state analogue mechanism or a noncompetitive or uncompetitve agonism or antagonism or the action is by a nonreceptor mediated mechanism including a xe2x80x9ccounterfeit incorporation mechanismxe2x80x9d.
The chemical and physical properties of the Luminide agents such as permeance and reactivity to different oxidoreductase enzymes, electron carriers, or different free radicals including those of oxygen are exploited to control the environment into which C is released. Permeance of the Luminide agent to the blood brain barrier or cell membranes, or affinity of the Luminide agent to plasma proteins which results in a decreased excretion rate relative to free C, or lack of reactivity of extracellular enzymes with the Luminide agent relative to free C are exemplary mechanism where by Luminides provide for the release of active free C in the proper biological compartment or in the presence of the target receptor so that the desired therapeutic change is achieved. Thus, Luminides serve as therapeutic drugs. And, the present invention, Luminides, a broad class of pharmaceutical agents comprises antilipidemic drugs, anticholesterol drugs, contraceptive agents, anticoagulants, anti-inflamatory agents, immuno-suppressive drugs, antiarrhythmic agents, antineoplastic drugs, antihypertensive drugs, epinephrine blocking agents, cardiac inotropic drugs, antidepressant drugs, diuretics, antifungal agents, antibacterial drugs, anxiolytic agents, sedatives, muscle relaxants, anticonvulsants, agents for the treatment of ulcer disease, agents for the treatment of asthma and hypersensitivity reactions, antithroboembolic agents, agents for the treatment of muscular dystrophy, agents to effect a therapeutic abortion, agents for the treatment of anemia, agents to improve allograft survival, agents for the treatment of disorders of purine metabolism, agents for the treatment of ischemic heart disease, agents for the treatment of opiate withdrawal, agents which activate the effects of secondary messenger inositol triphosphate, agents to block spinal reflexes, and antiviral agents including a drug for the treatment of AIDS.
Electron transferring and transporting elements are ubiquitous and are necessary for life. All eukaryotic and prokaryotic organisms depend on electron transferring and transporting elements which include metal containing hemes and nonmetal containing molecules such as flavins to convert the energy stored in the chemical bonds of foodstuffs into a form utilizable for the maintenance of the highly negative entropic state of life. The chemical energy conversion process generally involves a coupled series of electron carriers which is called an electron transport chain.
Free radicals of oxygen are produced during aerobic respiration in mitochondria as electrons are carried by electron carriers of the electron transport chain to the ultimate electron acceptor, oxygen, and superoxide and peroxide, partial reduction products of oxygen, are continuously produced during cytosolic hydroxylation and oxygenation reactions as well as during other reactions which involve enzymatic reduction of oxygen. The cytosol as well as mitochondria of aerobic cells contain high concentrations of the enzyme superoxide dismutase which converts superoxide into hydrogen peroxide and molecular oxygen. Oxygen radicals which include hydrogen peroxide and superoxide are found in greater concentration in the mitochondria relative to the cytosol because reduction of oxygen occurs to a greater extent in the former compartment; however, appreciable concentration are found in both compartments.
Luminides are agents which are permeant to the desired biological compartment which undergo an oxidation reduction reaction with the target cell""s electron carriers or react with free radicals produced as a consequence of electron transport and release a drug moiety into the desired compartment in active form to effect a greater therapeutic effect or therapeutic ratio relative to the free C agent as a consequence of altered pharmacokinetics or pharmacodynamics such as a desirable kinetics of release, a resistance to inactivation or excretion, greater solubility, enhanced absorption, a diminished toxicity, or greater access to the cellular or biological compartment which is the site of action of C.
Luminide agents are three or four part molecules where each part is a functionality with a defined purpose. Exemplary Luminides are 
where A represents a functionality which undergoes an oxidation reduction reaction where electrons are transferred directly between A and the target cell""s electron carriers or the electrons are transferred indirectly through an electron transfer functionality, D, which is described in more detail below. Alternatively, A represents a functionality which undergoes a reaction with free radicals of oxygen which are produced as a consequence of electron transport. An excited state is produced in A as a consequence of its participation in one of these reactions. Then A undergoes intramolecular energy transfer from its own excited state to the B functionality which is an energy acceptor. Upon receiving energy from A, B achieves an excited state which relaxes through heterolytic cleavage of the covalent bond of B with C where C is a drug moiety which is released into the environment. D serves as an electron transfer functionality which gains (loses) electrons from (to) the environment and donates (accepts) electrons to (from) A to activate it so that the energy of excited A is transferred to B with release of C as occurs for the three functionality case. In both cases, free C is a drug molecule. The released drug molecule effects a therapeutic functional change by a mechanism which comprises receptor mediated mechanisms including reversible and irrereversible competitive agonism or antagonism including a molecle known as a suicide substrate or a transition state analogue mechanism or a noncompetitive or uncompetitive agonism or antagonism or the action is by a nonreceptor mediated mechanism including a xe2x80x9ccounterfeit incorporation mechanismxe2x80x9d.
The energy donating funtionality, A, is a molecule which reacts as previously described to form an excited state of high enough energy so that this subsequently transferred energy is of sufficient magnitude to break the covalent bond between the drug functionality, C, and the energy acceptor functionality, B. Chemiluminescent molecules can form highly excited states of the proper magnitude of energy, can undergo oxidation reduction reactions or react with free radicals, and possess a metastable excited state from which intramolecular energy transfer can occur: thus, they can serve as the A functionality. In general, chemiluminescent molecules relevant to this invention can be placed into three categories: 1) molecules undergoing reaction involving peroxides and oxygen free radicals; 2) molecules undergoing reaction involving oxidation or reduction and 3) molecules undergoing both reaction with peroxides and oxygen free radicals followed by an oxidation or reduction reaction. Molecules of the first category include Lophine and its derivatives, acridinium esters and acridans, tetraphenylpyrrole, phthalhydrazides, acyloins, biacridinium salts, vinylcarbonyls, vinylnitriles, tetrakis (dimethylamino) ethylene, acylperoxides, indoles, tetracarbazoles and active oxalates. Molecules belonging to the second category include ruthenium chelates 2, 6-diaminopyrene, or cation radicals and molecules which follow a Chemically Initiated Electron Exchange Luminescence mechanism such as certain dioxetans and dioxetanones. Dioxene derivatives belong to the third category. They form a dioxetan by reation with superoxide and then produce efficient chemiluminescence by a CIEEL mechanism.
As an example from the first category, the chemiluminescent compound, luminol, has a chemiluminescent maximum in the region 390-400 nm in an aqueous solution. Chemiluminescence is produced by the reaction of luminol with oxygen free radicals where a large fraction of the product molecules are formed in their excited state. The nature of the excited state is electronic, and it has a mean lifetime of the order of 10xe2x88x928 seconds which is typically ten thousand times the period of a molecular vibration. Emission involves a quantum mechanically allowed singlet to singlet transition with energy of the order of 75 Kcal/mole. The quantum yield for forming the excited electronic state is 0.5. Because luminol undergoes a chemiluminescent reaction with oxygen radicals, this compound has been used as a molecular probe for these radicals by linkage to a molecule which directs the probe to a cellular compartment. For example, when luminol is attached to carnitine, the probe is transported into mitochondria and the intensity of chemiluminescence produced is proportional to the magnitude of electron transport activity which produces oxygen radicals. The chemiluminescent molecule, lucigenin, is also used as a probe for oxygen free radicals.
As for members of the second category, chemiluminescent molecules which undergo a redox reaction to produce an excited state react directly with electron carriers of the cell or undergo a redox reaction with the electron transfer functionality D.
As for the third category, a D functionality is optional. A chemiluminescent molecule of this category reacts with oxygen free radicals and forms an excited state, and chemiluminescence is produced but properties such as quantum yield or the relative ratio of singlet to triplet excited state can be altered by the transfer of electrons involving for example a D functionality. See Table 1 below for chemiluminescent molecules.
Exemplary energy acceptor molecules include those which demonstrate photochromic behavior with electromagnetic radiation and bleaching agents. If the A functionality is chemiluminescent, then the B functionality is such that the photodissociative drug release spectrum of B overlaps the chemiluminescence spectrum of A.
Triarylmethane dyes react with cyanide to form nitrites called leucocyanides which liberate cyanide ion with a quantum yield of approximately one when irradiated with UV light in the wavelength range of 250 to 320 nm. 
The spectrum of the photorelease reaction of cyanide ion can be extended to longer wavelengths in the case of triarylmethane dyes by substitutions of a naphthylene for an aryl group and also by using cationic polymethine dyes. The latter form nitriles, which are thermally stable, by the reaction of the carbonium ion of the dye with cyanide. The formation of the nitrile causes the colored dye to be bleached as is the case with triarylmethane dyes, and cyanide is released as the dye becomes colored upon absorption of 320-415 nm. Reversible bleaching by an agent and coloration by light is photochromic behavior.
Cationic dyes demonstrate this behavior and include di and triarylmethane dyes, triarylmethane lactones and cyclic ether dyes, cationic indoles, pyronines, phthaleins, oxazines, thiazines, acridines, phenazines, and anthocyanidins, and cationic polymethine dyes and azo and diazopolymethines, styryls, cyanines, hemicyanines, dialkylaminopolyenes, and other related dyes. See Table 2 below for structures for salt isomerism-type photochromic dyes. These photochromic molecules form covalent bonds with a number of agents called bleaching agents because they convert the compounds from colored to colorless form during bond formation. Bleaching agents are diverse and include hydroxide, cyanide, azide, bisulfide, and sulfite compounds, thiocyanate, ferrocyanide, chromate, tetraborate, acetate, nitrite, carbonate, citrate, aluminate, tungstate, molybdate, methoxide, 2-methoxyethoxide, cinnamate, and p-methoxycinnamate salts, and thiols and amines.



Brilliant Milling Blue B
Brilliant Blue F and R Ex. 
Di-4(N,N-dietylamine)phenyl[-4-(N,N-diethyl-amine-2-methyl) phenyl] methyl carbonium 
Tri-[4(N,N-dipropylamino)phenyl] methyl carbonium 
Di-[4(N,N-diethylamino)phenyl]-[4(ethylamino)-phenyl] methyl carbonium 
Di-[4(N,N-diethylamino)phenyl]-[4(N,N-diethyl-amino)naphthyl] methyl carbonium 
Di-[4(N,N-dimethylamino)phenyl]-[4(hydroxy)phenyl] methyl carbonium 
Tri-[4(N-propylamino)phenyl] methyl carbonium 
Hectolene Blue DS-1398
Hectolene Blue DS-1823
Sevron Brilliant Red 4 G
Di-[4(N,N-dimethylamino)phenyl]-[4(hydroxy)phenyl methyl carbonium 
Tri-[4(N-propylamino)phenyl] methyl carbonium 
Hectolene Blue DS-1398
Hectolene Blue DS-1823
Sevron Brilliant Red 4 G
Genacryl Red 6 B
Genacryl Pink G
Sevron Brilliant - Red B
Sevron Brilliant - Red 3 B
1,5-bis-[4(N,N-dimethylamino)phenyl]-1,5-bis-(phenyl)divinyl carbonium trifluoroacetate 
1,1,3,3-tetrakis[4(N,N-dimethylamino)phenyl] vinyl carbonium perchlorate 
1,5-bis-[4(N,N-dimehtylamino)phenyl]-1,5-bis-(phenyl) divinyl carbonium p-toluenesulfonate 
1,7-bis-[4(N,N-dimethylamino)phenyl]-1,7-bis-(2,4-dichlorophenyl) trivinyl carbonium per-chlorate 
Di-[4(N,N-dimethylamino)phenyl vinyl]-2,4-di-phenyl-6-methane thiopyran] methyl carbonium perchlorate 
1,7-bis-[4-(N,N-dimethylamino)phenyl]-1,7-bis-(4-chlorophenyl) trivinyl carbonium trifluoro-acetate 
1.1,3-tris-[4-(N,N-dimethylamino)phenyll divinyl carbonium perchlorate 
1,1,7,7-tetrakis-[4-(N,N-dimethylamino)phenyl] trivinyl carbonium perchlorate 
1,3-bis-[4-(N,N-dimethylamino)phenyl]-1,3-bis-(phenyl) vinyl carbonium perchlorate 
1,1,5,5-tetrakis-[4-(N,N-diemthylamino)phenyl] divinyl carbonium perchlorate 
1,5-bis-[4-(N,N-dimethylamino)phenyl]-1,5-bis-(phenyl) divinyl carbonium perchlorate 
1,7-bis-[4-(N,N-dimethylamino)phenyl]-1,7-bis-(phenyl) trivinyl carbonium trifluoroacetate 
1(1,3,3-trimethyl indoline)-2-[4-(N,N-dimethyl-amino)phenyl] ethylene carbonium perchlorate 
1(1,3,3-trimethyl indoline)-4-[4-(N,N-dimethyl-amino)phenyl] butylene carbonium perchlorate 
1,1,3,3-tetrakis-[4(N,N-diethylamino)phenyl] vinyl carbonium perchlorate 
1,1-bis-[4-(N,N-diethylamino)phenyl]-3,3-bis-[4-(N,N-dimethylamino)phenyl] vinyl carbonium perchlorate 
1,1,5,5-tetrakis-[4-(N,N-diethylamino)phenyl] divinyl carbonium perchlorate 
1,1-bis-[4-(N,N-dimethylamino)phenyl]-3-[4-(amino) phenyl]-3-methylvinyl carbonium perchlorate 
Tris-[1,1-bis-[4(N,N-dimethylamino)phenyl] ethylene] methyl carbonium perchlorate 
Tris-[1,1-bis-4-(N,N-diethylamino)phenyl] ethylene] methyl carbonium perchlorate 
1,1,5-tris-[4-(N,N-dimethylamino)phenyl] divinyl carbonium Perchlorate 
N[4-(N,N-dimethylamino) cinnamylidene] auramine 
1,1-bis-[4-(N,N-dimethylamino)phenyl-3,4-bis-(phenyl)]-3,4-diazo butene carbonium 
1,1,5,5-tetrakis-[4-(N,N-dimethylamino)phenyl]-2,3-diazo pentene carbonium 
N-(Nxe2x80x2,Nxe2x80x2-dimethylamino cinnamylidene)-N,N-diphenyl ammonium 
Azo Polymethines
Dyes of the general structural type 
Photochromic diazopolymethines 
1,1,5,5-tetrakis-[4-(N,Np-dimethylamino)phenyl]-2,3-diazo pentene carbonium 
1,1-bis-[4-(N,N-dimethylamino)phenyl-3,4-bis-(phenyl)]-3,4-diazo butene carbonium
The drug functionality, C, includes any molecule which exhibits bleaching behavior with the B functionality and has an increased therapeutic effect or therapeutic ratio as a consequence of its delivery as part of a Luminide agent. For example, Foscarnet, a viral reverse transcriptase inhibitor possesses both a carboxylate and phosphate group which will bleach photochromic compounds; 4-bromocrotonyl-CoA, an acetoacetyl -CoA thiolase inhibitor, possesses a thiol group which will bleach photochromic compounds; L-3-iodo-xcex1- methyltyrosine, a tyrosine hydroxylase inhibitor, possesses a carboxylate group which will bleach photochromic compounds, and captopril, an antihypertensive pharmaceutical, possesses both a sulfide and carboxylate group which will bleach photochromic compounds. Furthermore, the pharmacokinetics and/or pharmacodynamics of these agents are altered via delivery to the site of action by way of a luminide agent such that the therapeutic effect or therapeutic ratio is enhanced.
Other drugs which are not inherently photochromic bleaches in that they lack a nucleophilic group which will form a reversible covalent bond with the B functionality can be derivatized with a known bleaching nucleophilic group such as cinnamate, sulfite, phosphate, carboxylate, thiol, or amine group to transform them into bleaching agents of the B functionality such as a cationic dye. See Table 3 below for the structure of a exemplary drug molecules.
The electron transfer functionality, D, includes molecules which undergo a redox reaction which transfers electrons between the electron carriers and the A functionality where a redox reaction of a results in its activation to an excited energy state. The D functionality can be a natural electron carrier such as ubiquinone or a synthetic electron carrier such as methylene blue, phenazine methosulfate, or 2,6-dichlorophenolindophenol. Structures of electron transfer molecules appear below in Table 4.
A representative luminide is the product of the covalent linkage of the polymethine dye with a bleaching drug such as Foscarnet and with a chemiluminescent reactive molecule such as luminol. This conjugate represents a molecule which releases Foscarnet in the presence of oxygen free radicals. The energy of the reaction of luminol with oxygen radicals undergoes intramolecular electronic energy transfer by radiative and nonradiative mechanisms. The latter dominate and include coulombic interactions, dipole-dipole resonance, and exchange interaction. These processes increase the quantum yield for drug release above that which would be produced by luminescence transfer alone. For example, Forster, in a quantum mechanical treatment of resonance transfer, in the region of spectral overlap involving allowed transitions of two well separated molecules has only considered dipole-dipole interactions in deriving an experimentally verified formula which predicts a distance of 5-10 nm as the distance at which transfer and spontaneous decay of the excited donor are equally probable. The formula predicts the transfer probability is inversely proportional to the separation distance raised to the sixth power. However, the donor and accepter functionalities of a Luminide are covalently linked; thus, since the separation distance is of the order of angstroms, the transfer probability is great. In fact, the efficiency of transfer has been studied in certain molecules which consist of two independent chromophores separated by one or more saturated bonds. In such cases, energy transfer over large distances has been observed to be in agreement with predictions from Forster""s Theory.
The Luminides can be prepared by known reactions where necessary, appropriate derivatives of the subunits are formed before coupling.
Representative examples of appropriate derivatization and coupling reactions are given in the following examples, illustrating the preparation of representative Luminides. These examples are not to be taken as an exhaustive listing, but only illustrative of the possibilities according to the present invention.
Luminides synthesis involves the chemical joining of three or four functionalities. A representative luminide of three functionalities comprises an energy donor molecule such as a chemiluminescent molecule, an energy acceptor molecule such as a photochromic molecule, and a drug. A representative luminide of four functionalities comprises the mentioned three functionalities and also an electron transfer functionality which can undergo an oxidation reduction reaction.
A three group Luminde can be formed by condensing a photochromic dye functionalized as an acid chloride with a chemiluminescent molecule possessing an alcoholic or amino group to form an ester or amide. The luminide pharmaceutical is then formed by addition of the drug bleaching agent. An exemplary pathway of this type appears in example 1.
Alternatively, the chemiluminescent or/and electron transfer functionality can be linked to the energy acceptor functionality by formation of an ester or amide where the former functionality/functionalities is/are an acid halide as demonstrated in example 15.
Also, functionalities of the electron transfer and energy donor type can be linked to the energy acceptor part by an acylation reaction as demonstrated in examples 2, 3 and 8; by nucleophillic substitution as demonstrated in examples 4, 5, 6, 7, 9, 10, 12 and 17; by a carbanion mechanism as demonstrated in example 11; by a Grignard reaction as demonstrated in example 14, by a tosylate mechanism as demonstrated in example 13, or by a Wittig reaction as demonstrated in example 16. Similar reaction pathways can be used to link chemiluminescent molecules to energy donor molecules. The list of examples of reaction pathways is intended to be examplary and other pathways can be devised by one skilled in the art. Furthermore, only a representative number of luminides are shown and a vast number of other novel luminides can be made by one skilled in the art following the guidelines herein disclosed.
And, the disclosed exemplary luminides, and components: chemiluminescent molecules, photochromic molecules, energy transfer molecules, and drug molecules can be modified to further candidate components by addition of functional groups by one skilled in the art. Representitive groups include aklyl, cycloalkl, alkoxycarbonyl, cyano, carbamoyl, heterocyclic rings containing C, O, N, S, sulfo, sulfamoyl, alkoxysulfonyl, phosphono, hydroxyl, halogen, alkoxy, alkylthiol, acyloxy, aryl, alkenyl, aliphatic, acyl, carboxyl, amino, cyanoalkoxy, diazonium, carboxyalkylcarboxamido, alkenyl, thio, cyanoalkoxycarbonyl, carbamoylalkoxycarbonyl, alkoxy carbonylamino, cyanoalkylamino, alkoxycarbonylalkylamino, sulfoaklylamino, alkylsulfamoylaklylamino, oxido, hydroxy alkyl, carboxy alkylcarbonyloxy, cyanoalkyl, carbonyloxy, carboxyalkylthio, arylamino, heteroarylamino, alkoxycarbonyl, alkylcarbonyloxy, carboxyalkoxy, cyanoalkoxy, alkoxycarbonylalkoxy, carbamoylalkoxy, carbamoylalkyl carbonyloxy, sulfoalkoxy, nitro, alkoxyaryl, halogenaryl, amino aryl, alkylaminoaryl, tolyl, alkenylaryl, allylaryl, alkenyloxyaryl, allyloxyaryl, allyloxyaryl, cyanoaryl, carbamoylaryl, carboxyaryl, alkoxycarbonylaryl, alkylcarbonyoxyaryl, sulfoaryl, alkoxysulfoaryl, sulfamoylaryl, and nitroaryl.
Synthesis
Synthesis of MTL 7-3, and MTL J-1
Step A: Preparation of p-N,N-dimethylaminobenzoyl chloride 
In a round bottom flask fitted with a reflux condenser is placed 4 g of p-dimethylaminobenzoic acid and 8 ml of oxalylchloride. The evolution of gas starts immediately and the spontaneous reaction is run at room temperature for 15 minutes. 8 ml of toluene is added and and the mixture is heated to gentle reflux for one hour. The reaction mixture is then distilled to dryness under reduced pressure to produce a blue-green solid which is washed with ether and dried on a watch glass.
Step B: Preparation of p-dimethylaminobenzanilide 
A solution of 0.95 g of aniline in 10 ml of dry ether containing 2.2 g of K2CO3 was heated to reflux temperature. To the refluxing mixture 2 g of p-dimethylaminobenzoyl chloride was added as a powder slowly through the condenser port. The reaction was refluxed for 1.5 hours and the ether distilled off. Cold water was added to the residue and the p-dimethylaminobenzanilide collected by filtration. Yield 1.51 g orange-red powder. Anilide functionality confirmed by IR.
Step C: Preparation of p-N,N dimethyl-p-N-ethyl-N-2-chloroethylbenzophenone. 
1.5 g of dry, powdered p-dimethylbenzanilide, 2.4 g of N-ethyl-N-2-chloroethylaniline, and 1.3 ml of phosphorus oxychloride were mixed in a 25 ml 2-necked flask, fitted with a thermometer immersed in the reation mixture and a reflux condenser having a CaCl2 drying tube on top. The reaction was warmed slowly until an exothermic reaction occured. The temperature was maintained at less than 100xc2x0 C. by periodic immersion of the flask in ice water. The reaction was then maintained at 95xc2x0 C. for one hour to yield a dark green liquid. The reaction mixture was then hydrolyzed in a 150 ml beaker with the addition of a solution of 1.36 ml of concentrated HCl to 10.4 ml of distilled H2O. The beaker was covered with a watch glass and heated on a hot water bath for 1.5 hours to yield a green-yellow solution.
10:1 cold water was added to the hydrolyzed mixture to form a brilliant purple solution which was filtered. The filtered product was dissolved in a minimum volume of ethanol, and twice the volume of cold H2O was added. The ketone was then extracted in an equal volume of chloroform which was removed by distillation to dryness under reduced pressure. Brilliant purple solid product. Ketone confirmed by IR and NMR.
Step D: Preparation of 1-(4-N,N-dimethylaminophenyl)-1-(4-N-ethyl-N-2-chloroet hylphenyl) ethylene. 
One ml of a 3 molar etherial solution of magnesium bromide was evaporated almost to dryness under reduced pressure in a 50 ml three necked flask equipped with a thermometer and nitrogen sparger. The grey moist solution was suspended in 1.3 ml of dry benzene. The flask was then equipped for refluxing by the addition of a condenser fitted with a CaCl2 drying tube and an addition funnel. 0.017 moles of the ketone dissolved in 4.4 ml of boiling benzene was then placed in an addition funnel and added dropwise to the warmed methyl magnesium bromide-benzene slurry over a half hour period. The resulting solution was refluxed for one hour. The completion of the reaction was evident by the color change of the solution from brilliant purple to blue. The reaction mixture was cooled to room temperature, and 0.785 ml of saturated NH4Cl was cautiously added. Additional NH4Cl was added until two layers were apparent with the blue alcohol product in the bottom H2O layer. 1.7xc3x9710xe2x88x923 g of p-toluenesulphonic acid was added, and the solution was boiled on a water bath with the addition of benzene until the evaporation of H2O was complete and only the benzene layer remained. The acid contained in the reaction mixture was then removed by the addition of 0.73xc3x9710xe2x88x923 g of sodium bicarbonate. The solvent was reduced to dryness under reduced pressure to yield light blue crystals.
Step E: Preparation of a perchlorate of 1,5-di-(p-N-2-chloroethyl-N-ethylaminophenyl)-1,5-bis-(p-N,N-dimethylaniline)-1,3-pentadiene. 
A mixture of 8.7xc3x9710xe2x88x924 moles of 1-(4-N,N-dimethylaminophenyl)-1-(4-N-2-chloroethyl-N-et hylaminophe-nyl)ethylene, 0.13 ml of ethyl orthoformate, and 0.39 ml of acetic anhydride was treated with a solution of 0.035 ml of 72 percent perchloric acid and 0.35 ml of acetic acid previouly cooled to 0xc2x0 C. The resulting mixture was allowed to stand at room temperature for 8 days, after which time it was treated with 0.22 ml of ether and kept an additional day at room temperature. The condensation product was washed with acetic acid, ethanol, and ether. The pale blue-green crystals were dissolved in a minimum volume of warm dry ethanol. The solution was centrifuged to pellet a white precipitate. The dark blue supernatant solution was removed and distilled to dryness under reduced pressure. The blue crystals where placed on watch glass and placed in the dark. The structure of the condensation compound was confirmed by IR and NMR.
Step F: Preparation of 1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethyl isolminol)-N-ethylaminophenyl)-1,5-bis-(p-N,N-dimethyla niline)-1,3-pentadiene. 
5 mg (1.8xc3x9710xe2x88x925 moles) of N-(4-aminobutyl)-N-ethylisoluminol was suspended in 0.1 ml of pyridine in a small test tube. 30 mg (3.6xc3x9710xe2x88x925 moles) of the pentadiene was dissolved in 0.5 ml of pyridine and 0.25 ml of DMSO. This latter solution was added dropwise to the former while vigorously stirring at room temperature initially then with intermittant imersion in a water bath at 35xc2x0 C. The isoluminol which was only slightly soluble in pyridine went into solution as the reaction progressed. The reaction mixture was stirred and intermittantly immersed in the water bath at 35xc2x0 C. until the reaction was complete. This reaction and all subsequent reactions were protected from direct light.
Step G: Preparation of Luminide, MTL 7-3 (2,6-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-e thylamino-phenyl)-2,6-bis-(p-N,N-dimethylanilino)-3,5-hexadinenit rile). 
5 mg of solid KCN and 1 ml of distilled H2O were added to the blue-grey solution of 1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-et hylaminophe-nyl)-1,5-bis-(p-N,N-dimethylanilino)-1,3-pe ntadiene in pyridine/DMSO solvent. The solution was acidified by addition of sulphuric acid and the evolving HCN gas was removed by evaporating the solvent to dryness under reduced pressure. The pale green crystals were redissolved in DMSO to yield a pale green liquid. IR and NMR confirmed the structure.
Step H: Preparation of Luminide MTL J-1 (5-phosphonoformate-1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-1,5-bis-(p-N,N-dimethylaniline)-1,3-pentadiene). 
MTL J-1 was prepared by the equimolar addition of disodium phosphonoformate dissolved in H2O to a DMSO solution of 1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-1,5-bis(p-N,N-dimethylaniline)-1,3-pentadiene such that the final solvent was 4:3 DMSO/H2O. The reaction mixture was protected from light, and the colorless reaction product solution was packaged in light protecting vials and refrigerated at 4xc2x0 C.
Methods of synthesis of triphenylmethane dyes appear in Appendix I.
Methods of synthesis of polymethine dyes appear in Appendix II.
Methods of synthesis of azo and diazopolymethine dyes appear in Appendix III and IV, respectively.
Methods of synthesis of quaternary ammonium salt poly methines appear in Appendix V.
Methods of synthesis of the intermediates, tetramethylortho carbonate and substituted ethylenes appear in Appendix VI.
Methods of synthesis of indoline based dyes appear in Appendix VII.
Methods of synthesis of dyes with more than one chromophore appear in Appendix VIII.
Methods of forming a leucocyanide appear in Appendix IX.